Safety and immunogenicity of a recombinant protein RBD fusion heterodimer vaccine against SARS-CoV-2.

In response to COVID-19 pandemic, we have launched a vaccine development program against SARS-CoV-2. Here we report the safety, tolerability, and immunogenicity of a recombinant protein RBD fusion heterodimeric vaccine against SARS-CoV-2 (PHH-1V) evaluated in a phase 1-2a dose-escalation, randomized clinical trial conducted in Catalonia, Spain. 30 young healthy adults were enrolled and received two intramuscular doses, 21 days apart of PHH-1V vaccine formulations [10 µg (n = 5), 20 µg (n = 10), 40 µg (n = 10)] or control [BNT162b2 (n = 5)]. Each PHH-1V group had one safety sentinel and the remaining participants were randomly assigned. The primary endpoint was solicited events within 7 days and unsolicited events within 28 days after each vaccination. Secondary endpoints were humoral and cellular immunogenicity against the variants of concern (VOCs) alpha, beta, delta and gamma. All formulations were safe and well tolerated, with tenderness and pain at the site of injection being the most frequently reported solicited events. Throughout the study, all participants reported having at least one mild to moderate unsolicited event. Two unrelated severe adverse events (AE) were reported and fully resolved. No AE of special interest was reported. Fourteen days after the second vaccine dose, all participants had a >4-fold change in total binding antibodies from baseline. PHH-1V induced robust humoral responses with neutralizing activities against all VOCs assessed (geometric mean fold rise at 35 days p < 0.0001). The specific T-cell response assessed by ELISpot was moderate. This initial evaluation has contributed significantly to the further development of PHH-1V, which is now included in the European vaccine portfolio.ClinicalTrials.gov Identifier NCT05007509EudraCT No. 2021-001411-82.

Preclinical evaluation of PHH-1V vaccine candidate against SARS-CoV-2 in non-human primates.

SARS-CoV-2 emerged in December 2019 and quickly spread worldwide, continuously striking with an unpredictable evolution. Despite the success in vaccine production and mass vaccination programs, the situation is not still completely controlled, and therefore accessible second-generation vaccines are required to mitigate the pandemic. We previously developed an adjuvanted vaccine candidate coded PHH-1V, based on a heterodimer fusion protein comprising the RBD domain of two SARS-CoV-2 variants. Here, we report data on the efficacy, safety, and immunogenicity of PHH-1V in cynomolgus macaques. PHH-1V prime-boost vaccination induces high levels of RBD-specific IgG binding and neutralizing antibodies against several SARS-CoV-2 variants, as well as a balanced Th1/Th2 cellular immune response. Remarkably, PHH-1V vaccination prevents SARS-CoV-2 replication in the lower respiratory tract and significantly reduces viral load in the upper respiratory tract after an experimental infection. These results highlight the potential use of the PHH-1V vaccine in humans, currently undergoing Phase III clinical trials.

Immunogenicity and safety in pigs of PHH-1V, a SARS-CoV-2 RBD fusion heterodimer vaccine candidate.

The continuing high global incidence of COVID-19 and the undervaccinated status of billions of persons strongly motivate the development of a new generation of efficacious vaccines. We have developed an adjuvanted vaccine candidate, PHH-1V, based on a protein comprising the receptor binding domain (RBD) of the Beta variant of SARS-CoV-2 fused in tandem with the equivalent domain of the Alpha variant, with its immunogenicity, safety and efficacy previously demonstrated in mouse models. In the present study, we immunized pigs with different doses of PHH-1V in a prime-and-boost scheme showing PHH-1V to exhibit an excellent safety profile in pigs and to produce a solid RBD-specific humoral response with neutralising antibodies to 7 distinct SARS-CoV-2 variants of concern, with the induction of a significant IFNγ+ T-cell response. We conclude that PHH-1V is safe and elicits a robust immune response to SARS-CoV-2 in pigs, a large animal preclinical model.

Exploring FeLV-Gag-Based VLPs as a New Vaccine Platform-Analysis of Production and Immunogenicity.

Feline leukemia virus (FeLV) is one of the most prevalent infectious diseases in domestic cats. Although different commercial vaccines are available, none of them provides full protection. Thus, efforts to design a more efficient vaccine are needed. Our group has successfully engineered HIV-1 Gag-based VLPs that induce a potent and functional immune response against the HIV-1 transmembrane protein gp41. Here, we propose to use this concept to generate FeLV-Gag-based VLPs as a novel vaccine strategy against this retrovirus. By analogy to our HIV-1 platform, a fragment of the FeLV transmembrane p15E protein was exposed on FeLV-Gag-based VLPs. After optimization of Gag sequences, the immunogenicity of the selected candidates was evaluated in C57BL/6 and BALB/c mice, showing strong cellular and humoral responses to Gag but failing to generate anti-p15E antibodies. Altogether, this study not only tests the versatility of the enveloped VLP-based vaccine platform but also sheds light on FeLV vaccine research.

Safety and immunogenicity of the protein-based PHH-1V compared to BNT162b2 as a heterologous SARS-CoV-2 booster vaccine in adults vaccinated against COVID-19: a multicentre, randomised, double-blind, non-inferiority phase IIb trial.

Background: A SARS-CoV-2 protein-based heterodimer vaccine, PHH-1V, has been shown to be safe and well-tolerated in healthy young adults in a first-in-human, Phase I/IIa study dose-escalation trial. Here, we report the interim results of the Phase IIb HH-2, where the immunogenicity and safety of a heterologous booster with PHH-1V is assessed versus a homologous booster with BNT162b2 at 14, 28 and 98 days after vaccine administration. Methods: The HH-2 study is an ongoing multicentre, randomised, active-controlled, double-blind, non-inferiority Phase IIb trial, where participants 18 years or older who had received two doses of BNT162b2 were randomly assigned in a 2:1 ratio to receive a booster dose of vaccine-either heterologous (PHH-1V group) or homologous (BNT162b2 group)-in 10 centres in Spain. Eligible subjects were allocated to treatment stratified by age group (18-64 versus ≥65 years) with approximately 10% of the sample enrolled in the older age group. The primary endpoints were humoral immunogenicity measured by changes in levels of neutralizing antibodies (PBNA) against the ancestral Wuhan-Hu-1 strain after the PHH-1V or the BNT162b2 boost, and the safety and tolerability of PHH-1V as a boost. The secondary endpoints were to compare changes in levels of neutralizing antibodies against different variants of SARS-CoV-2 and the T-cell responses towards the SARS-CoV-2 spike glycoprotein peptides. The exploratory endpoint was to assess the number of subjects with SARS-CoV-2 infections ≥14 days after PHH-1V booster. This study is ongoing and is registered with ClinicalTrials.gov, NCT05142553. Findings: From 15 November 2021, 782 adults were randomly assigned to PHH-1V (n = 522) or BNT162b2 (n = 260) boost vaccine groups. The geometric mean titre (GMT) ratio of neutralizing antibodies on days 14, 28 and 98, shown as BNT162b2 active control versus PHH-1V, was, respectively, 1.68 (p < 0.0001), 1.31 (p = 0.0007) and 0.86 (p = 0.40) for the ancestral Wuhan-Hu-1 strain; 0.62 (p < 0.0001), 0.65 (p < 0.0001) and 0.56 (p = 0.003) for the Beta variant; 1.01 (p = 0.92), 0.88 (p = 0.11) and 0.52 (p = 0.0003) for the Delta variant; and 0.59 (p ≤ 0.0001), 0.66 (p < 0.0001) and 0.57 (p = 0.0028) for the Omicron BA.1 variant. Additionally, PHH-1V as a booster dose induced a significant increase of CD4+ and CD8+ T-cells expressing IFN-γ on day 14. There were 458 participants who experienced at least one adverse event (89.3%) in the PHH-1V and 238 (94.4%) in the BNT162b2 group. The most frequent adverse events were injection site pain (79.7% and 89.3%), fatigue (27.5% and 42.1%) and headache (31.2 and 40.1%) for the PHH-1V and the BNT162b2 groups, respectively. A total of 52 COVID-19 cases occurred from day 14 post-vaccination (10.14%) for the PHH-1V group and 30 (11.90%) for the BNT162b2 group (p = 0.45), and none of the subjects developed severe COVID-19. Interpretation: Our interim results from the Phase IIb HH-2 trial show that PHH-1V as a heterologous booster vaccine, when compared to BNT162b2, although it does not reach a non-inferior neutralizing antibody response against the Wuhan-Hu-1 strain at days 14 and 28 after vaccination, it does so at day 98. PHH-1V as a heterologous booster elicits a superior neutralizing antibody response against the previous circulating Beta and the currently circulating Omicron BA.1 SARS-CoV-2 variants in all time points assessed, and for the Delta variant on day 98 as well. Moreover, the PHH-1V boost also induces a strong and balanced T-cell response. Concerning the safety profile, subjects in the PHH-1V group report significantly fewer adverse events than those in the BNT162b2 group, most of mild intensity, and both vaccine groups present comparable COVID-19 breakthrough cases, none of them severe. Funding: HIPRA SCIENTIFIC, S.L.U.

Preclinical evaluation of a COVID-19 vaccine candidate based on a recombinant RBD fusion heterodimer of SARS-CoV-2.

Current COVID-19 vaccines have been associated with a decline in infection rates, prevention of severe disease, and a decrease in mortality rates. However, SARS-CoV-2 variants are continuously evolving, and development of new accessible COVID-19 vaccines is essential to mitigate the pandemic. Here, we present data on preclinical studies in mice of a receptor-binding domain (RBD)-based recombinant protein vaccine (PHH-1V) consisting of an RBD fusion heterodimer comprising the B.1.351 and B.1.1.7 SARS-CoV-2 variants formulated in SQBA adjuvant, an oil-in-water emulsion. A prime-boost immunisation with PHH-1V in BALB/c and K18-hACE2 mice induced a CD4+ and CD8+ T cell response and RBD-binding antibodies with neutralizing activity against several variants, and also showed a good tolerability profile. Significantly, RBD fusion heterodimer vaccination conferred 100% efficacy, preventing mortality in SARS-CoV-2 infected K18-hACE2 mice, but also reducing Beta, Delta and Omicron infection in lower respiratory airways. These findings demonstrate the feasibility of this recombinant vaccine strategy.

Reset observers alleviating the peaking and the robustness tradeoffs: A case study on force estimation in teleoperation.

The peaking phenomenon is an undesirable effect appearing in observers and destroying controller performance. Several solutions have been proposed to mitigate peaking in state estimation. The literature shows that reset or impulsive observers are superior to linear (Luenberger) observers. However, the comparisons are based on particular choices of linear observers. This paper investigates this issue. First, comparative frameworks are proposed based on two traded-off performance indices: ensemble maximum-peak versus ensemble settling time for nominal conditions, and ensemble settling time versus size of the error asymptotic invariant set for quadratically bounded uncertain plants. Next, performance limitations of linear observers are represented by Pareto-optimal boundaries. In this way, not previously considered in the literature as far as known, the superiority of the chosen reset observer is more rigorously assessed. The framework is finally applied to force estimation in haptic teleoperation.

Reset Controller Design Based on Error Minimization for a Lane Change Maneuver.

An intelligent vehicle must face a wide variety of situations ranging from safe and comfortable to more aggressive ones. Smooth maneuvers are adequately addressed by means of linear control, whereas more aggressive maneuvers are tackled by nonlinear techniques. Likewise, there exist intermediate scenarios where the required responses are smooth but constrained in some way (rise time, settling time, overshoot). Due to the existence of the fundamental linear limitations, which impose restrictions on the attainable time-domain and frequency-domain performance, linear systems cannot provide smoothness while operating in compliance with the previous restrictions. For this reason, this article aims to explore the effects of reset control on the alleviation of these limitations for a lane change maneuver under a set of demanding design conditions to guarantee a suitable ride quality and a swift response. To this end, several reset strategies are considered, determining the best reset condition to apply as well as the magnitude thereto. Concerning the reset condition that triggers the reset action, three strategies are considered: zero crossing of the controller input, fixed reset band and variable reset band. As far as the magnitude of the reset action is concerned, a full-reset technique is compared to a Lyapunov-based error minimization method to calculate the optimal reset percentage. The base linear controller subject to the reset action is searched via genetic algorithms. The proposed controllers are validated by means of CarSim.

Basic Send-on-Delta Sampling for Signal Tracking-Error Reduction.

This paper investigates the dynamic selection of an appropriate threshold for basic Send-on-Delta (SoD) sampling strategies, given an available transmission rate to reduce the signal tracking-error. The paper formulates the error-reduction principle and proposes an algorithm that calculates, in real time, the amplitude threshold value (also called delta value) for a desired mean transmission rate. The algorithm is implemented to be computed in a Send-on-Delta driver and is tested with three signals that match the step response of a second order control system. Comparison results with a conformant periodic transmission strategy reveals that it improves deeply the tracking-error while maintaining the desired average throughput.

Structural Identifiability of Dynamic Systems Biology Models.

A powerful way of gaining insight into biological systems is by creating a nonlinear differential equation model, which usually contains many unknown parameters. Such a model is called structurally identifiable if it is possible to determine the values of its parameters from measurements of the model outputs. Structural identifiability is a prerequisite for parameter estimation, and should be assessed before exploiting a model. However, this analysis is seldom performed due to the high computational cost involved in the necessary symbolic calculations, which quickly becomes prohibitive as the problem size increases. In this paper we show how to analyse the structural identifiability of a very general class of nonlinear models by extending methods originally developed for studying observability. We present results about models whose identifiability had not been previously determined, report unidentifiabilities that had not been found before, and show how to modify those unidentifiable models to make them identifiable. This method helps prevent problems caused by lack of identifiability analysis, which can compromise the success of tasks such as experiment design, parameter estimation, and model-based optimization. The procedure is called STRIKE-GOLDD (STRuctural Identifiability taKen as Extended-Generalized Observability with Lie Derivatives and Decomposition), and it is implemented in a MATLAB toolbox which is available as open source software. The broad applicability of this approach facilitates the analysis of the increasingly complex models used in systems biology and other areas.

Robust Stability of Scaled-Four-Channel Teleoperation with Internet Time-Varying Delays.

We describe the application of a generic stability framework for a teleoperation system under time-varying delay conditions, as addressed in a previous work, to a scaled-four-channel (γ-4C) control scheme. Described is how varying delays are dealt with by means of dynamic encapsulation, giving rise to mu-test conditions for robust stability and offering an appealing frequency technique to deal with the stability robustness of the architecture. We discuss ideal transparency problems and we adapt classical solutions so that controllers are proper, without single or double differentiators, and thus avoid the negative effects of noise. The control scheme was fine-tuned and tested for complete stability to zero of the whole state, while seeking a practical solution to the trade-off between stability and transparency in the Internet-based teleoperation. These ideas were tested on an Internet-based application with two Omni devices at remote laboratory locations via simulations and real remote experiments that achieved robust stability, while performing well in terms of position synchronization and force transparency.

Use of chemostat cultures mimicking different phases of wine fermentations as a tool for quantitative physiological analysis.

BACKGROUND: Saccharomyces cerevisiae is the most relevant yeast species conducting the alcoholic fermentation that takes place during winemaking. Although the physiology of this model organism has been extensively studied, systematic quantitative physiology studies of this yeast under winemaking conditions are still scarce, thus limiting the understanding of fermentative metabolism of wine yeast strains and the systematic description, modelling and prediction of fermentation processes. In this study, we implemented and validated the use of chemostat cultures as a tool to simulate different stages of a standard wine fermentation, thereby allowing to implement metabolic flux analyses describing the sequence of metabolic states of S. cerevisae along the wine fermentation. RESULTS: Chemostat cultures mimicking the different stages of standard wine fermentations of S. cerevisiae EC1118 were performed using a synthetic must and strict anaerobic conditions. The simulated stages corresponded to the onset of the exponential growth phase, late exponential growth phase and cells just entering stationary phase, at dilution rates of 0.27, 0.04, 0.007 h-1, respectively. Notably, measured substrate uptake and product formation rates at each steady state condition were generally within the range of corresponding conversion rates estimated during the different batch fermentation stages.Moreover, chemostat data were further used for metabolic flux analysis, where biomass composition data for each condition was considered in the stoichiometric model. Metabolic flux distributions were coherent with previous analyses based on batch cultivations data and the pseudo-steady state assumption. CONCLUSIONS: Steady state conditions obtained in chemostat cultures reflect the environmental conditions and physiological states of S. cerevisiae corresponding to the different growth stages of a typical batch wine fermentation, thereby showing the potential of this experimental approach to systematically study the effect of environmental relevant factors such as temperature, sugar concentration, C/N ratio or (micro) oxygenation on the fermentative metabolism of wine yeast strains.

Dolor de espalda en trabajadores de un hospital de mutua / Back pain among workers in a benefit hospital

Se ha realizado un estudio descriptivo basado en el análisis de las historias clínicas de los trabajadores del hospital que consultaron por dolor de espalda entre enero de 2002 y diciembre de 2008. Ha consultado el 28,3% de los trabajadores. El 31,8% de ellos fueron auxiliares sanitarios; el 24,7%, DUE, y el 21,2%, administrativos. La media de edad fue de 44,6 años. La mayoría de la patología que se diagnosticó fue del tipo artrosis y/o discopatía. Se identificaron periodos de IT en el 28,2% de los trabajadores que consultaron, y al 50% de estos trabajadores se les diagnosticó patología, concentrándose la mayor parte en la columna lumbar (83,3%). La duración de los días de baja estuvo entre 27,7 y 91,7 días (IC 95%). El tratamiento de mayor prescripción fue el médico y rehabilitador. Además de confirmar la relación entre patología y edad, evidenciamos la importancia clínica del dolor de espalda en los trabajadores de nuestro hospital (AU)

We performed a descriptive study based on review of medical records of hospital workers who consulted for back pain between January/2002 and December/2008. It was found that 28.3% of hospital workers consulted for back pain. They were nursing assistants (31.8%), nurses (24.7%), administrative (21.2%) and other. The mean age was 44.6 years old. Most of the pathology diagnosis was by osteoarthritis and/or discopathy. Among the workers who have consulted, 28.3% had some period of temporary work incapacity. 50% of these workers had pathology, located mostly in the lumbar spine (83.3%). The duration of days of incapacity ranged from 27.7 to 91.7 days. The most prescribed treatment was medical and rehabilitation. Besides confirming the relationship between pathology of spine and age, we show the clinical importance of back pain among workers in our hospital (AU)

Análisis crítico de un proyecto de investigación sobre trastornos musculoesqueléticos: lumbalgia: determinación de contingencia en una MATEPSS / Critical analysis a research Project on musculo-skeletal disorders: Low bank pain contingency asessment at one matepss

El objetivo es valorar un estudio realizado sobre la lumbalgia, su determinación de contingencia, es decir, si su origen es de etiología laboral o extralaboral, y determinar la magnitud de la lumbalgia como contingencia profesional en los trabajadores atendidos en la MATEPSS, en el año 2007, en tres provincias (Lleida, Girona y Tarragona). Se realiza un análisis del estudio descriptivo, retrospectivo y transversal. Mide variables de manera independiente, los porcentajes de casos que cursaron baja, el grupo profesional, la edad, el sexo, el mecanismo lesional, los casos derivados al sistema público de salud, así como las pruebas complementarias de imagen más frecuentes. Su utilidad está dirigida a una población similar a la estudiada. Presenta limitaciones en cuanto a la estimación de la causalidad, y del riesgo, así como la asociación entre El objetivo es valorar un estudio realizado sobre la lumbalgia, su determinación de contingencia, es decir, si su origen es de etiología laboral o extralaboral, y determinar la magnitud de la lumbalgia como contingencia profesional en los trabajadores atendidos en la MATEPSS, en el año 2007, en tres provincias (Lleida, Girona y Tarragona). Se realiza un análisis del estudio descriptivo, retrospectivo y transversal. Mide variables de manera independiente, los porcentajes de casos que cursaron baja, el grupo profesional, la edad, el sexo, el mecanismo lesional, los casos derivados al sistema público de salud, así como las pruebas complementarias de imagen más frecuentes. Su utilidad está dirigida a una población similar a la estudiada. Presenta limitaciones en cuanto a la estimación de la causalidad, y del riesgo, así como la asociación entre (AU)

The aim of the present work is to assess a study on low back pain and its contingency findings (that is, whether its origin is occupational or non-occupational), and to assess the importance of low back pain as an occupational contingency among workers seen in the year 2007 at one MATEPSS encompassing three northern Spanish provinces, namely Lérida, Gerona and Tarragona.The study analyzed was descriptive, retrospective and cross-sectional and considered, as independent variables, the percentages of cases granted sick leave, the occupational groups concerned, the age, the gender, the causative mechanism, the percentage of cases referred to the Public Health Care System, and the most commonly applied complementary image examinations. It is concluded that the study might be useful as a reference for a population similar to the studied one; it evidences limitations in the areas of causality, risk andinter-variables association estimation. Conflicts of interest may arise, though, in fact, they did not do so in this case. The results might lead to the postulation of hypotheses that might then be verified and expanded (AU)

Situación de la enfermedad profesional en una mutua, en el año previo al cambio legislativo / Occupational disease in a mutual insurance company in the year before the legistlative change

El 10 de noviembre de 2006, se publica el nuevo cuadro de EE PP en España, estableciéndose nuevos criterios de notificación y registro. Objetivo: Cuantificar las EE PP de la población trabajadora cubierta por la mutua ASEPEYO durante el último año previo al cambio legislativo, y describir sus principales características. Metodología: Estudio descriptivo de los casos de enfermedad profesional declarados por la mutua ASEPEYO en el año 2006. Resultados: Durante el año 2006, se observó una incidencia de 171 nuevos casos por cada 100.000 trabajadores, que constituye un total de 3.824 casos de EE PP con baja. El 99% de los casos fueron leves. El 89,5% de los casos declarados pertenecen al grupo de EE PP causadas por agentes físicos. Conclusiones: Se observa en 2006 una disminución de casos con respecto a años anteriores. La mayoría de los casos presentan un pronóstico leve y la patología por agentes físicos es la más frecuente (AU)

Background: The new Panel of Occupational Diseases was published in Spain on November 10th 2006, establishing new criteria for notification and registration. Aims and purposes: To assess and quantify the occupational diseases among the labour population covered by the “ASEPEYO” mutual insurance company over the last year before the legislative change, and to describe their main features. Methods: Descriptive study of the cases of occupational disease declared by “ASEPEYO” over the year 2006. Results: Over the year 2006 there was an occupational disease incidence of 171 cases per 100,000 workers, representing a total number of 3,824 cases of medical leave-associated occupational disease. 99% of the cases were classed as mild. 89.5% of the reported cases were classed among the occupational diseases caused by physical agents. Conclusions: Over the year 2006, a decrease as compared to preceding years is evident. Most of the cases were mild, and physical agents were the main cause (AU)